Fluorinated imidazoline benzodioxane, preparation and therapeutic uses thereof

ABSTRACT

The present invention relates to novel fluorinated benzodioxane imidazoline derivatives, to their preparation and to their therapeutic applications. 
     The invention is directed more particularly toward the compounds corresponding to the structure of general formula 1:                    
     in which: 
     R represents a linear, branched or cyclized alkyl or alkenyl group containing 1 to 7 carbon atoms, or a benzyl group, and 
     the fluorine atom can occupy position 5, 6, 7 or 8, in their racemic form and their dextrorotatory and levorotatory pure enantiomeric forms, and also the addition salts thereof.

This is a 371 of PCT/FR00/01835, filed Jun. 29, 2003.

The present invention relates to novel fluorinated benzodioxaneimidazoline derivatives corresponding to formula 1.

in which:

R represents a linear, branched or cyclized alkyl or alkenyl groupcontaining 1 to 7 carbon atoms, or a benzyl group,

the fluorine atom on the homocycle can occupy position 5, 6, 7 or 8.

The invention relates to the racemic and enantiomerically pure forms, tothe salified forms thereof and also to the process for preparing them.

The invention also relates to the use of these compositions as medicinalproducts, and also to the preparation of a medicinal product used as anα₂-adrenergic receptor antagonist and intended in this respect to treatneurodegenerative diseases, and also their progression.

Advantageously, the radical R is a methyl group, an ethyl group, ann-propyl group, an isopropyl group, an isobutyl group, acyclopropylmethyl group, an allyl group or a benzyl group.

Preferably, the fluorine atom occupies position 5.

It has been shown (Mavridis, Neuroscience (1991), 41, 507) that thelocus coeruleus plays a predominant role in the recovery of dopaminergicfunctions altered by administration of MPTP to monkeys. Its destructionbrings about a reduction in recovery. Moreover, compounds withα₂-antagonist action are shown as reducing Parkinson's symptoms inmonkeys (Colpaert, Brain Res. Bull., 26, 627, 1991) or in rats(Colpaert, Neuropharmacology, 26, 1431, 1987) by elevating the releaseof dopamine (Marien, M., Colpaert, F. Effect of (+)-efaroxan on mousestriatal dopamine metabolism in vivo. DOPAMINE 94-Satellite Meeting ofthe XIIth Int. Congr. Pharmacology, Quebec City, Canada, Jul. 20-24,1994).

Furthermore, an α₂-antagonist, idazoxan, is shown as having beneficialaction on the deleterious effects of cerebral ischemia (Gustafson, Exp.Brain Res., 86, 555, 1991 et J. Cereb. Blood Flow Metab., 1990, 10, 885)and also in progressive supranuclear paralysis and neurodegenerativedisease (Ghika, Neurology, 41, 986, 1991). It has also been shown thatcompounds with α₂-antagonist activity induce an increase in the releaseof acetylcholine in the prefrontal cortex (Tellez, J.Neurochem. (1997),68, 778).

Thus, a substance activating the noradrenergic system may have theproperty of opposing the progression of the degeneration of the involvedneurons, by reactivating the various cerebral localization systems,whether they are dopaminergic or cholinergic, or whether this involvesthe release of growth factors (Fawcett et al. J. Neurosci. (1998), 18,2808-2821). These compounds are thus useful in cases ofneurodegenerative diseases of the type such as Parkinson's disease orAlzheimer's disease and their progression, Huntington's chorea,amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, progressivesupranuclear paralysis, cognitive and memory disorders, attentiondeficit and vigilance deficit in the elderly, and also the progressionor evolution of these diseases or disorders. Ischemic and post-ischemiccerebral disorders, cerebrovascular accidents and consequences thereof,depression, narcolepsy and male sexual dysfunctions are also concerned,as are disorders associated with acquired immunodeficiency syndrome.

It is known that benzodioxane derivatives such as idazoxan:2-(1,4-benzodioxan-2-yl)-2-imidazoline, or alkoxy idazoxan:2-(2-alkoxy-1,4-benzodioxan-2-yl)-2-imidazoline, have α₂-antagonistproperties (J. Med. Chem. (1983), 26, 823; J. Med. Chem. (1985), 28,1054). These compounds have been patented in GB 2 068 376 for idazoxanand in EP 92328 for alkoxy-idazoxans.

It has been shown in these publications that a large number of idazoxanderivatives have been synthesized and tested for their agonist orantagonist action on the α₁ or α₂ receptors, inter alia, halogenatedderivatives, substituted on the aromatic nucleus, have all been found tobe less active than or inactive relative to their unsubstituted idazoxananalog (in particular the 6/7-fluoro, chloro or bromo derivative,5,8-dichloro or 8-chloro derivative). Moreover, the 2-methoxy idazoxanderivative substituted in 6,7 with two methoxy groups showed onlyextremely marginal activity as an α₂-presynaptic antagonist.

The compounds of the present invention differ from the known compoundsin that they have a fluorine atom in position 5, 6, 7 or 8 of thearomatic nucleus. They have the property of being powerful α₂-adrenergicreceptor antagonists.

It has been found, remarkably, that the presence of this fluorine atomin these positions gives these molecules particularly advantageousproperties when compared with their nonfluorinated analog.

The pharmacological properties of the products of the present inventionhave been studied, inter alia, in comparison with those of 2-methoxyidazoxan (RX 821002) and 2-ethoxy idazoxan (RX 811059), which arestructurally related compounds that are derivatives not substituted onthe aromatic nucleus.

Specifically, we show, in vivo, the superiority of the pharmacologicalproperties of the products of the present invention in the test ofmemory deficit induced with scopolamine, of the antagonism of thehypothermia induced with guanabenz, an α₂-agonist substance, and on thelevel, in the cortex, of normetanephrine, a metabolite and selectivemarker for the release of noradrenalin.

Test of the memory deficit induced with scopolamine:

In accordance with the cholinergic hypothesis of the phenomena oflearning and memory, scopolamine has amnesiant properties in animals andman. Its administration to a healthy person induces certain amnesiasymptoms similar to those observed in Alzheimer's disease. It has beenproposed that the scopolamine be used as an experimental pharmacologicalmodel of this pathology. The similarities between the memory deficits ofAlzheimer's disease and those induced with scopolamine in rats have beenpublished (P. Chopin et M. Briley, The effects of raubasine anddihydroergocristine on an agerelated deficit in passive avoidancelearning in rats, J.Pharm.Pharmacol. 42, 375-376, 1990). Scopolaminereduces the capacity for acquisition, memorization and recall in a testof passive avoidance in rats. This involves measuring the reticence,after learning, that the animal has in entering a dark compartment,where it receives a mild electric shock. The administration ofscopolamine suppresses this reticence, and the test compounds oppose theeffect of scopolamine.

The comparison of the products of the present invention is made with theknown compound RX 821002, dextrorotatory enantiomer. The experimentalprotocol is that published by P. Chopin and M. Briley (Effects of fournon-cholinergic cognitive enhancers in comparison with tacrine andgalanthamine on scopolamine-induced amnesia in rats: Psychopharmacology,106, 26-30, 1992).

The results are given in the following table:

MEMORY DEFICIT INDUCED WITH SCOPOLAMINE Increase in the time taken toenter the dark compartment by Compounds the treated animals, relativeActive doses over the to those receiving range from 0.04 to scopolaminealone. 2.5 mg/kg. (% amplitude of the effect) (+) RX 821002non-significant Dextrorotatory compound 201% of Example 1 Dextrorotatorycompound 198% of Example 2 Tacrine 191% Donepezil  67%

The compounds of the present invention show appreciable activity over awide range of doses, in contrast with (+) RX 821002, which is notsignificantly active. The amplitude of its effect is at least as largeas that of tacrine, and more active than that of donepezil, referencecompounds used therapeutically for Alzheimer's disease.

The value and the appreciable difference of the products of theinvention is thus shown.

Inhibition of the hypothermia induced with Guanabenz:

The assessment of the biological activity of the compounds of theinvention is also carried out in vivo by studying the inhibition of thehypothermia induced with a central α₂-agonist such as guanabenzaccording to the protocol of S. C. Dilsaver, Pharmacol. Biochem. Behav.,45, 247, 1993.

This test demonstrates the antagonist effect of the α₂-adrenergicreceptors, in vivo, of the compounds of the invention, and also theiractivity at the central level. The inhibitory capacities are expressedas the ED₅₀ which represent the doses producing a significant inhibitionof the hypothermia induced with guanabenz on the one hand, and anormalization, that is to say a return to the normal temperature for theanimal, before injection of guanabenz on the other hand. These valuesare obtained using the method of J. T. Litchfield and F. Wilcoxon (J.Pharmacol. Exp. Ther., 96, 99, 1949). The comparison is made between the2-methoxy compounds, fluorinated in position 5 (dextrorotatory compoundof Example 1) and nonfluorinated: (+) RX 821002, and between the2-ethoxy, fluorinated in position 5 (dextrorotatory compound of Example2) and nonfluorinated: (+) RX 811059.

Dextrorotatory (+) RX compound of 821002 Example 1 Range of active doses0.01-10 0.0025-40 (i.p) 0.01 0.003 Inhibition (mg/kg) ED₅₀ (mg/kg)Normalization (mg/kg)  0.04-2.5 0.0025-10 ED₅₀ (mg/kg) 0.05 0.02 Rangeof active doses (per 0.16-10  0.04-40 os) normalization (mg/kg) 0.560.22 ED₅₀ (mg/kg) Dextrorotatory (+) RX compound of 811059 Example 2Range of active doses 0.04-10 0.0025-40 (i.p) 0.08 0.02 Inhibition(mg/kg) ED₅₀ (mg/kg) Normalization (mg/kg) 0.16-10  0.01-10 ED₅₀ (mg/kg)0.32 0.16

The greater power of action of the compounds of the invention comparedwith their analogs (+) RX 821002 and (+) RX 811059 is thus seen. Theamplitude of the action is also demonstrated by the determination of thedoses inducing the inhibition of hypothermia in 100% of the animals, on6 doses (each dose separated by a factor of 4) for the dextrorotatorycompound of Example 1 against 2 doses for (+) RX 821002. Similarly, thedextrorotatory compound of Example 1 normalizes the hypothermia in 100%of the animals on 3 doses, whereas (+) RX 821002 does not, it does so ononly 80% of the animals and at only 2 doses.

(+) RX Dextrorotatory 821002 compound of Example 1 Doses inhibiting the0.16 and 0.01-0.04-0.16-0.63- hypothermia in 100% of 2.5 mg/kg 2.5-10mg/kg the animals Doses normalizing the none 0.16-0.63-2.5 mg/kghypothermia in 100% of the animals

It is thus seen that the products of the invention have a very broadrange of active doses, and are thus better α₂-adrenergic antagonists.

Release of noradrenalin:

The level of normetanephrine, a noradrenalin metabolite, in the cerebraltissues is used as a measurement of the release of noradrenalin. Wood,P. L. and coll. Pharmacological Rev. 40, 163-187, (1988), and J.Neurochem. 48, 574-579, (1987)). The formation of normetanephrine, bythe action of catechol O-methyltransferase takes place on the outside ofthe noradrenergic neurones and its measurement takes account ofvariations in the release of noradrenalin. This measurement is performedin the frontal cortex, a region innervated mainly by the locuscoeruleus.

The test compound is administered intraperitoneally to the mice, whichare sacrificed after 60 minutes by irradiation with microwaves (to avoidany artefactual changes in the metabolite levels). After dissection,normetanephrine is assayed by HPLC on the cortical tissue extracts. Atdoses of 0.01 to 2.5 mg/kg, the assayed normetanephrine represents alevel from 125 to 150% higher with the compound of Example 1, relativeto (+) RX 821002, under the same conditions. This shows the greaterefficacy of this compound compared with (+) RX 821002 for the release ofnoradrenalin.

Binding to the α₂-adrenergic receptors in vitro:

It was also confirmed that the compounds of the invention have affinityfor the human α₂-adrenergic receptors, at the nanomolar level on thebasis of tests of binding to the subtypes of these receptors, usingtritiated 2-methoxy-idazoxan, [³H] RX821002, as radioactive ligand (J.C. Devedjian and coll. Eur.J.Pharmacol. (1994), 252, 43-49).

The in vivo tests show the advantage which may be afforded bysubstitution with a fluorine atom on the aromatic nucleus relative tothe compound devoid of this substitution.

Since the compounds of the present invention contain an asymmetriccarbon, they are in a dextrorotatory form and a levorotatory form. Thepresent invention thus relates also to the enantiomerically purecompounds, to the addition salts thereof and also to pharmaceuticalcompositions comprising at least one compound of formula 1 and asuitable excipient. The pharmaceutical compositions may be presented ina suitable manner, for oral, injectable or parenteral administration, inthe form of wafer capsules, gel capsules, tablets or injectablepreparations, at a daily dose of from 0,1 to 200 mg.

The compounds of the present invention may be prepared from3-fluorocatechol, (described in J.Amer.Chem.Soc. 77, 5314-5317, 1955) bycoupling with 2,3-dibromopropionamide in acetonitrile in the presence ofK₂CO₃ to give the 2 regioisomers 5- and8-fluoro-1,4-benzodioxane-2-carboxamide. Several recrystallizations makeit possible to isolate the 5-fluoro derivative in pure form, at theexpense of the 8-fluoro derivative which is more soluble under theseconditions. The amide function in position 2 of the benzodioxane isdehydrated into nitrile. This nitrile is then brominated by the actionof NBS to give the bromonitrile, which is subjected to the action of asodium alkoxide such as sodium methoxide in methanol, to form theintermediate imidate which reacts in situ with ethylenediamine to formthe desired α-methoxyimidazoline derivative. In a similar manner, thevarious alkoxy derivatives in position 2 are obtained by treating thepreceding bromonitrile derivative by treatment with a correspondingalkali metal alkoxide.

The 2 enantiomers may be separated in several ways: either bydiastereoselective crystallization with a chiral acid which may betartaric acid or derivatives thereof such as dibenzoyltartaric acid, orby chromatographic separation, preparative HPLC, on a chiral phase,giving the dextrorotatory isomer and the levorotatory isomer, thehydrochloride of which may be obtained in crystalline form by the usualmethods.

The 6- and 7-fluoro derivatives on the aromatic ring are obtained from(6- or 7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-yl)methanol, described inJ. Med. Chem. (1987), 30, 814. These methanol derivatives are oxidizedto acid and then amidated and dehydrated to nitrile according to theprocesses described in J. Med. Chem. (1983), 26, 823, or J. Med. Chem.(1985), 28, 1054, and then treated as indicated above.

The procedures for the various stages of the synthesis illustrate theinvention:

EXAMPLE 1 2-(5-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline

Stage 1: 5-Fluoro-1,4-benzodioxane-2-carboxamide.

A solution containing 50 g of 3-fluorocatechol (391 mmol), 99.3 g of2,3-dibromopropionamide (430 mmol, 1.1 eq.) and 108.1 g of groundpotassium carbonate (782 mmol, 2 eq.) in 400 ml of acetonitrile isheated at 60° C. for 16 hours. The reaction mixture is filtered and thefiltrate is then evaporated to dryness. 70.5 g of a pale yellow solidare obtained (92% yield; 1/1 mixture of the two regioisomers).Successive recrystallizations from hot ethanol give 16.7 g of pure5-fluoro-1,4-benzodioxane-2-carboxamide (22% yield).

Melting point: 167° C. ¹H NMR (400 MHz, CDCl₃):6.86-6.71 (m, 3H,aromatics); 6.52 (broad s, 1H, NH); 6.11 (broad s, 1H, NH); 4.72 (dd,J=2.4 and 7.2 Hz, 1H, H2); 4.62 (dd, J=2.4 and 11.6 Hz, 1H, H3A); 4.23(dd, J=7.2 and 11.6 Hz, 1H, H3B).

Stage 2: 5-Fluoro-1,4-benzodioxane-2-carbonitrile

13.7 ml of pyridine (169 mmol, 2 eq.) are added to a suspension of 16.7g of amide from Stage 1 (84.5 mmol) in 180 ml of dioxane at 0° C.,followed, 10 minutes later, by dropwise addition of 13.1 ml oftrifluoroacetic anhydride (19.5 g; 93 mmol, 1.1 eq.). The reactionmixture is kept cold for 1 hour and is then stirred at room temperaturefor 16 hours. The solution is taken up in Et₂O/1N HCl. The organic phaseis washed with 1N NaOH, dried over MgSO₄, filtered and then evaporatedto dryness. 16.8 g of a pale yellow oil are obtained (quantitativeyield).

¹H NMR (400 MHz, CDCl₃): 6.90-6.73 (m, 3H, aromatics); 5.15 (dd, J=3.6and 2.4 Hz, 1H, H2); 4.50 (dd, J=11.6 and 3.6 Hz, 1H, H3A); 4.41 (dd,J=11.6 and 2.4 Hz, 1H, H3B).

Stage 3: 5-Fluoro-2-bromo-1,4-benzodioxane-2-carbonitrile

A solution containing 6.44 g of the nitrile obtained in Stage 2 (36mmol), 6.40 g of NBS (36 mmol, 1 eq.), and 100 mg of benzoyl peroxide in200 ml of CCl₄ is heated at 70° C. for 48 hours. The mixture is allowedto cool to room temperature. The reaction mixture is then filtered. Thesolid is washed with CCl₄ and the mother liquors are evaporated todryness. 9.3 g of an orange-yellow oil are isolated (quantitativeyield).

¹H NMR (400 MHz, CDCl₃): 6.93 (m, 2H, aromatics); 6.81 (m, 1H,aromatic); 4.62 (d, J=11.6 Hz, 1H, H3A); 4.48 (d, J=11.6 Hz, 1H, H3B).

Stage 4: 2-(5-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline

A solution containing 7 g of2-bromo-5-fluoro-1,4-benzodioxane-2-carbonitrile (27.1 mmol) and 220 mgof sodium methoxide (4 mmol, 0.15 eq.) in 150 ml of methanol are stirredat room temperature for % hour. 2 ml of ethylenediamine (1.79 g, 29.8mmol, 1.1 eq.) are then added, followed by 11.3 ml of a 3N HCl/iPrOHsolution (34 mmol, 1.25 eq.). The reaction mixture is stirred at roomtemperature for 16 hours and then taken up in a 1N NaOH/CH₂Cl₂ mixture.The organic phase is dried over MgSO₄, filtered and then evaporated todryness. The crude product is purified by chromatography on silica underpressure (96/4 CH₂Cl₂/MeOH). 3.9 g of pure product are obtained (57%yield).

Melting point: 134° C. ¹H NMR (400 MHz, CDCl₃): 6.86-6.74 (m, 3H,aromatics) 5.14 (broad s, 1H, NH); 4.57 (d, J=11.2 Hz, 1H, H3A); 4.00(d, J=11.2 Hz, 1H, H3B); 3.75 (very broad multiplet, 4H, imidazoline);3.39 (s, 3H, OCH₃).

The hydrochloride is obtained by dissolving 500 mg of base in ether,followed by addition of 661 ml of a 3N HCl/iPrOH solution. The solidformed is filtered off, washed with ether and then dried under vacuum.480 mg of salt are obtained.

Melting point >260° C. Elemental analysis: Theoretical: C(49.40) H(4.89)N(9.70); Experimental: C(49.42) H(4.91) N(9.61).

The racemic compound in base form (2 g) is chromatographed by successiveinjections of an amount of from 500 to 800 mg, onto a Prochrompreparative HPLC column of diameter 50 mm (Chiralpack AD), eluting withan 85/15/0.001 hexane/isopropanol/diethylamine mixture. With a flow rateof 100 ml/min, the dextrorotatory and levorotatory enantiomers of theexample are successively isolated. The hydrochlorides of the enantiomersare precipitated from ether by adding a stoichiometric amount of ethanolsaturated with hydrogen chloride gas.

In particular:

(+) enantiomer:

[α_(D)]^(23°)=+90.80 (c=0.58, MeOH).

Melting point: sublimation from 230° C.

Elemental analysis (C₁₂H₁₃N₂O₃F, HCl):

Theoretical: C(49.92) H(4.89) N(9.70);

Experimental: C(49.94) H(4.77) N(9.57).

(−)enantiomer:

[α_(D)]^(23°)=−93.90 (c=0.43, MeOH).

Melting point: sublimation from 230° C.

Elemental analysis (C₁₂H₁₃N₂O₃F, HCl):

Theoretical: C(49.92) H(4.89) N(9.70);

Experimental: C(49.89) H(4.83) N(9.61).

EXAMPLE 2 2-(5-Fluoro-2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline.

115 mg of sodium are dissolved in 200 ml of ethanol, 8.52 g of2-bromo-5-fluoro-1,4-benzodioxane-2-carbonitrile (33 mmol), obtainedfrom Stage 3 of Example 1, are then added and the mixture is stirred atroom temperature for ¾ hour. 2.43 ml of ethylenediamine (2.18 g; 36.3mmol; 1.1 mol. eq.) are then added, followed by 13.8 ml of a 3NHCl/iPrOH solution (41.3 mmol, 1.25 mol. eq.). The reaction mixture isstirred at room temperature for 16 hours and then taken up in a iNNaOH/CH₂Cl₂ mixture. The organic phase is dried over MgSO₄, filtered andthen evaporated to dryness. The crude product is purified bychromatography on silica under pressure (96/4 CH₂Cl₂/MeOH). 4.17 g ofpure product are obtained (48% yield).

¹H NMR (400 MHz, CDCl₃): 6.80 (m, 3H, aromatics); 5.14 (broad s, 1H,NH); 4.53 (d, J=11.2 Hz, 1H, H3A); 4.10 (d, J=11.2 Hz, 1H, H3B);3.97-3.45 very broad multiplet, 4H, imidazoline); 3.70 (m, 2H, OCH₂);1.12 (t, J=7.2 Hz, 3H, CH₃).

The two enantiomers are separated by chiral HPLC (Chiralpack AD column;96/4/0.1 hexane/iPrOH/diethyl-amine; 100 ml/min; 230 nm).

The hydrochlorides are obtained by dissolving the base in ether,followed by addition of a 3N HCl/iPrOH solution. The solid formed isfiltered off, washed with ether and then dried under vacuum.

(+) enantiomer:

[α_(D)]²⁴ (c=0.380; MeOH)=+80.9°.

Melting point >260° C.

Elemental analysis (C₁₃H₁₅N₂O₃F, HCl):

Theoretical: C(51.58) H(5.33) N(9.25);

Experimental: C(51.24) H(5.36) N(8.94).

(−) enantiomer:

[α_(D)]²⁴ (c=0.380; MeOH)=−77.6°.

Melting point >260° C.

Elemental analysis (C₁₃H₁₅N₂O₃F, HCl):

Theoretical: C(51.58) H(5.33) N(9.25);

Experimental: C(51.80) H(5.39) N(9.02).

The following compounds are obtained according to the same procedures asthose described above:

EXAMPLE 3 2-(5-Fluoro-2-propoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 11.02 (s, 2H, NH, HCl); 6.99 (m, 2H,aromatics); 6.92 (m, 1H, aromatic); 4.63 (d, J=11.5 Hz, 1H, H3A); 4.23(d, J=11.5 Hz, 1H, H3B); 3.99 (s, 4H, imidazoline); 3.55 (m, 2H, OCH₂);1.44 (m, 2H, OCH₂CH₂); 1.12 (t, J=7.2 Hz, 3H, CH₃).

Melting point: 206° C. Elemental analysis (C₁₄H₁₇N₂O₃F, HCl):Theoretical: C(53.09) H(5.73) N(8.84); Experimental: C(52.29) H(5.82)N(8.63).

EXAMPLE 4 2-(5-Fluoro-2-isopropoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 10.99 (s, 2H, NH, HCl); 6.99 (m, 2H,aromatics); 6.90 (m, 1H, aromatic); 4.59 (d, J=11.6 Hz, 1H, H3A); 4.18((d, J=11.6 Hz, 1H, H3B); 4.08 (m, 1H, OCH); 3.99 (s, 4H, imidazoline );1.18 (d, J=6 Hz, 3H, CH₃); 0.96 (d, J=6 Hz, 3H, CH₃).

Elemental analysis (C₁₄H₁₇N₂O₃F, HCl, ½ H₂O): Theoretical: C(51.55)H(5.82) N(8.30); Experimental: C(51.62) H(5.88) N(8.60).

EXAMPLE 5 2-(5-Fluoro-2-isobutoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 10.79 (s, 2H, NH, HCl); 6.97 m, 2H,aromatics); 6.90 (m, 1H, aromatic); 4.61 (d, J=11.4 Hz, 1H, H3A); 4.22(d, J=11.4 Hz, 1H, H3B); 3.97 (s, 4H, imidazoline); 3.37 (m, 2H, OCH₂);1.70 (m, 1H, CH); 0.75 (d, J=6.8 Hz, 3H, CH₃); 0.65 (d, J=6.8 Hz, 3H,CH₃).

Melting point: 206° C. Elemental analysis (C₁₅H₁₉N₂O₃F, HCl):Theoretical: C(54.47) H(6.09) N(8.47); Experimental: C(53.83) H(6.36)N(8.27).

EXAMPLE 62-(5-Fluoro-2-cyclopropylmethyloxy-1,4-benzo-dioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 10.98 (s, 2H, NH, HCl); 6.99 (m, 2H,aromatics); 6.90 (m, 1H, aromatic); 4.61 (d, J=11, 5 Hz, 1H, H3A); 4.22(d, J=11, 5 Hz, 1H, H3B); 3.98 (s, 4H, imidazolin); 3.44 (m, 2H, OCH₂);0.93(m, 1H, CH); 0.42 (m, 2H, cyclopropyl); 0.18 (m, 1H, cyclopropyl);0.00 (m, 1H, cyclopropyl).

Elemental analysis (C₁₅H₁₇N₂O₃F, HCl): Theoretical: C(54.80) H(5.52)N(8.52); Experimental: C(54.09) H(5.23) N(8.33).

EXAMPLE 7 2-(5-Fluoro-2-allyloxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 11.10 (s, 2H, NH, HCl); 6.99 (m, 2H,aromatics); 6.92 (m, 1H, aromatic); 5.78 (m, 1H, CH═CH₂); 5.25 (d,J=17.2 Hz, 1H, CH═CH₂); 5.13 (d, J=10.4 Hz, 1H, CH═CH₂) 4.68 (d, J=11.6Hz, 1H, H3A); 4.26 (d, J=11.6 Hz, 1H, H3B); 4.07 (m, 2H, OCH₂); 3.98 (s,4H, imidazoline).

Melting point: 214° C. Elemental analysis (C₁₄H₁₅N₂O₃F, HCl):Theoretical: C(53.43) H(5.12) N(8.90); Experimental: C(52.86) H(5.23)N(8.81).

EXAMPLE 8 2-(5-Fluoro-2-benzyloxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

¹H NMR (400 MHz, DMSO d6): 11.15 (s, 2H, NH, HCl); 7.30 (m, 3H,aromatics); 7.23 (m, 2H, aromatics); 6.99 (m, 2H, aromatics); 6.91 (m,1H, aromatic); 4.70 (m, 3H, H3A and PhCH₂); 4.29 (d, J=11.6 Hz, 1H,H3B); 3.96 (s, 4H, imidazoline).

Melting point: 218° C. Elemental analysis (C₁₈H₁₇N₂O₃F, HCl, H₂O):Theoretical: C(56.48) H(5.27) N(7.32); Experimental: C(56.50) H(5.31)N(7.21).

EXAMPLE 9 2-(6-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

This compound is prepared via2-(6-fluoro-2-methoxy-1,4-benzodioxan-2-yl)methanol described inJ.Med.Chem. (1987), 30, 814, and then converted into the imidazolineaccording to J.Med.Chem. (1983), 26, 823, or J.Med.Chem. (1985), 28,1054. Elemental analysis: (C₁₂H₁₃N₂O₃F, HCl).

EXAMPLE 10 2-(7-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

This compound is prepared via2-(7-fluoro-2-methoxy-1,4-benzodioxan-2-yl)methanol described inJ.Med.Chem. (1987), 30, 814, and then converted into the imidazolineaccording to J.Med.Chem. (1983), 26, 823, or J.Med.Chem. (1985), 28,1054. Elemental analysis: (C₁₂H₁₃N₂O₃F, HCl).

EXAMPLE 11 2-(8-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-imidazolineHydrochloride

Stage 1: 5/8-Fluoro-1,4-benzodioxane-2-carbonitrile:

15.8 ml of trifluoroacetic anhydride (23.4 g, 0.11 mol) are addeddropwise to a solution containing 20 g of5/8-fluorobenzodioxane-2-carboxamide, obtained in Stage 1 of Example 1,and 16.4 ml of pyridine (16.1 g, 0.2 mol) in 20 ml of dioxane maintainedat 0° C. in an ice bath. The reaction is kept cold for 2 hours and isthen extracted with Et₂O/lN HCl. The acidic phase is washed 3 times withether. The ether phases are dried over MgSO₄, filtered and thenevaporated to dryness. 16.34 g of a crude mixture are obtained, and arere-used in the following step without further purification.

Stage 2: 2-Bromo-8-fluoro-1,4-benzodioxane-2-carbonitrile:

A solution containing 16.34 g of5/8-fluoro-1,4-benzodioxane-2-carbonitrile (91.3 mmol), 17.87 g ofN-bromosuccinimide (100 mmol) and 200 mg of benzoyl peroxide in 500 mlof carbon tetrachloride is refluxed for 5 days. The reaction mixture iscooled to room temperature and the succinimide precipitate is thenremoved by filtration. The filtrate is evaporated to dryness to give22.2 g of a crude mixture containing2-bromo-5-fluoro-1,4-benzodioxane-2-carbonitrile and2-bromo-8-fluoro-1,4-benzodioxane-2-carbonitrile. The two isomers areseparated by flash chromatography on a column of silica (99.5/0.5petroleum ether/ethyl acetate). 7 g of2-bromo-5-fluoro-1,4-benzodioxane-2-carbonitrile and 6.2 g of thedesired 2-bromo-8-fluoro-1,4-benzodioxane-2-carbonitrile are obtained.

2-Bromo-8-fluoro-1,4-benzodioxane-2-carbonitrile:

¹H NMR (400 MHz, CDCl₃): 7.02 (m, 1H, aromatic ); 6.83 (m, 2H, aromatics); 4.58 (d, J=11.6 Hz, 1H, H3A ); 4.48 (d, J=11.6 Hz, 1H, H3B).

Stage 3: 2-(8-Fluoro-2-methoxy-1,4-benzodioxan-2-yl)-imidazoline

A solution containing 1.6 g of2-bromo-8-fluoro-1,4-benzodioxane-2-carbonitrile (6.2 mmol) and 40 mg ofsodium methoxide (0.7 mmol; 0.12 mol. eq.) in 50 ml of methanol arestirred at room temperature for ¾ hour. 0.456 ml of ethylenediamine(0.41 g; 6.8 mmol; 1.1 mol. eq.) is then added, followed by 2.3 ml of a3N HCl/iPrOH solution (6.8 mmol; 1.1 mol. eq.). The reaction mixture isstirred at room temperature for 16 hours and then taken up in a 1NNaOH/CH₂Cl₂ mixture. The organic phase is dried over MgSO₄, filtered andthen evaporated to dryness. The crude product is purified bychromatography on silica under pressure (96/4 CH₂Cl₂/MeOH). 0.75 g ofpure product is obtained (48% yield).

¹H NMR (400 MHz, CDCl₃): 6.85 (m, 1H, aromatic); 6.73(m, 2H, aromatics);4.57 (d, J=11.6 Hz, 1H, H3A); 4.00 (d, J=11.6 Hz, 1H, H3B); 3.76 (broadmultiplet, 4H, imidazoline); 3.42 (s, 3H, OCH₃).

¹³C NMR (100.03 Hz, CDCl₃): 162.34 (C quat. imidazoline), 151.99 (d,J=244 Hz, C8), 144.31 (C4a), 128.90 (d, J=14 Hz, C8a), 121.23 (d, J=9Hz, C6), 112.51 (d, J=3.7 Hz, C5), 108.79 (d, J=18 Hz, C7), 94.15 (C2),67.93 (C3), 51.58 (OCH₃), 50.5 (very broad multiplet, CH₂ imidazoline).

The hydrochloride is obtained by dissolving the base in ether and thenadding one equivalent of a 3N HCl/iPrOH solution. The solid formed isfiltered off, washed with ether and then dried under vacuum.

Elemental analysis: Theoretical C(49.92) H(4.89) N(9.70);

Experimental: C(49.63) H(4.93) N(9.54).

The bases enantiomers are separated by chiral HPLC (Chiralpack ADcolumn; 90/10/0.1 hexane/iPrOH/diethylamine; 100 ml/min; 254 nm).

The hydrochlorides are obtained by dissolving the base in ether and thenadding the equivalent of a 3N HCl/iPrOH solution. The solid formed isfiltered off, washed with ether and then dried under vacuum.

(+) enantiomer:

[α_(D)]²⁵ (c=0.253; MeOH)=+86.2°.

Melting point=262° C.

Elemental analysis (C₁₃H₁₅N₂O₃F₁, HCl):

Theoretical: C(49.92) H(4.89) N(9.70);

Experimental: C(49.70) H(4.87) N(9.56).

(−) enantiomer:

[α_(D)] ²⁵ (c=0.429; MeOH)=−85.8°.

Melting point =260° C.

Elemental analysis (C₁₃H₁₅N₂O₃F₁, HCl):

Theoretical: C(49.92) H(4.89) N(9.70);

Experimental: C(49.55) H(4.83) N(9.57).

The invention also covers the use of the compounds of formula 1 for thepreparation of a medicinal product such as an .₂-adrenergic receptorantagonist used and intended in this respect to treat neurodegenerativediseases and their progression, cognitive and memory disorders, and alsoattention deficit and vigilance deficit, Alzheimer's disease,Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis,Creutzfeld-Jacob disease, progressive supranuclear paralysis, and alsothe evolution of these diseases or disorders. Cerebral attacks, ischemicand post-ischemic cerebral disorders, depression, narcolepsy and malesexual dysfunctions are also concerned, as are disorders associated withacquired immunodeficiency syndrome. Finally, pathologies relating tocerebral attacks, to ischemic disorders, to cerebrovascular accidentsand their consequences, and also to depression, narcolepsy, male sexualdysfunctions, disorders associated with acquired immunodeficiencysyndrome, and also the evolution of these diseases or disorders, areconcerned.

What is claimed is:
 1. A compound corresponding to the structure ofgeneral formula 1:

in which: R represents a linear, branched or cyclized alkyl or alkenylgroup containing 1 to 7 carbon atoms, or a benzyl group, and thefluorine atom can occupy position 5, 6, 7 or 8, in their racemic formand their dextrorotatory and levorotatory pure enantiomeric forms, andalso the addition salts thereof.
 2. The compound of formula 1 as claimedin claim 1, characterized in that the radical R is a methyl group. 3.The compound of formula 1 as claimed in claim 1, characterized in thatthe radical R is an ethyl group.
 4. The compound of formula 1 as claimedin claim 1, characterized in that the radical R is an n-propyl group. 5.The compound of formula 1 as claimed in claim 1, characterized in thatthe radical R is a isopropyl group.
 6. The compound of formula 1 asclaimed in claim 1, characterized in that the radical R is an isobutylgroup.
 7. The compound of formula 1 as claimed in claim 1, characterizedin that the radical R is a cyclopropylmethyl group.
 8. The compound offormula 1 as claimed in claim 1, characterized in that the radical R isa allyl group.
 9. The compound of formula 1 as claimed in claim 1,characterized in that the radical R is a benzyl group.
 10. The compoundas claimed in claim 1, characterized in that the fluorine atom occupiesposition
 5. 11. A process for preparing the compounds of formula 1 asclaimed in claim 1, characterized in that 3-fluorocatechol is reactedwith 2,3-dibromo-propionamide, and the5-fluorobenzodioxane-2-carboxamide derivative obtained is crystallized,and is then dehydrated into nitrile, and then brominated with NBS,subjected to a treatment with a sodium alkoxide to form the intermediateimidate, which is then treated with ethylenediamine in an alcohol.
 12. Aprocess for preparing the compounds of formula 1 as claimed in claim 1,characterized in that 6- or7-fluoro-2,3-dihydro-benzo[1,4]dioxin-2-yl)methanol is converted intonitrile, and this nitrile is treated according to the process of claim11.
 13. A pharmaceutical composition, characterized in that it comprisesat least one compound of formula 1 as claimed in claim 1, and a suitableexcipient.
 14. A method of treating a person having a neurodegenerativedisease, comprising: administering the compound of formula 1 as recitedin claim 1 to the person.
 15. A method of treating a person having adisorder selected from one or more of cognitive disorders, memorydisorders, attention deficit disorders and vigilance deficit disorders;comprising: administering the compound of formula 1 as recited in claim1 to the person.
 16. A method of treating a person having Alzheimer'sdisease, comprising: administering the compound of formula 1 as recitedin claim 1 to the person.
 17. A method of treating a person having adisorder selected from one or more of Parkinson's disease, Huntington'schorea, amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, andprogressive supranuclear paralysis; comprising: administering thecompound of formula 1 as recited in claim 1 to the person.
 18. A methodof treating a person having a pathology selected from cerebral attacks,ischemic disorders, cerebrovascular accidents and their consequences,depression, narcolepsy, male sexual dysfunctions, and disordersassociated with acquired immunodeficiency syndrome; comprising:administering the compound of formula 1 as recited in claim 1 to theperson.
 19. A method of treating an animal having a neurodegenerativedisease, comprising: administering the compound of formula 1 as recitedin claim 1 to the animal.